Project Summary/Abstract (limit within 30 lines) The COVID-19 emerged in December 2019 and then spread rapidly over 214 countries. As of May 15, 2020, a total of more than 4.5M confirmed cases and over 300,000 deaths have been reported worldwide, posing significant health and economic threats to our society. Currently, an array of drugs approved for other indications have been studied, in addition to multiple investigational agents, for the treatment of COVID-19. Antivirals including remdesivir, favipiravir, chloroquine, and hydroxychloroquine have been rapidly tested in these clinical studies and demonstrated preliminary efficacy against COVID-19. However, these studies also revealed that a proportion of patients receiving remdesivir had significant adverse effects, including multiple-organ dysfunction syndrome, septic shock, and acute liver and kidney injury. Similarly, the use of chloroquine and hydroxychloroquine in COVID-19 patients has raised serious safety concerns including arrhythmias, cardiomyopathy, and retinopathy. These adverse effects are related to their wide distribution of drugs in the whole body after administration, causing damages in off-target vital organs. Therefore, tissue-specific delivery of antiviral therapeutics would ameliorate adverse effects while maintaining their efficacy to treat COVID-19. Our hypothesis that renal clearable ultrasmall nanocarriers can payload antiviral drugs selectively and deliver them to treat COVID-19 with reduced side effects. In our parent R01 (NIBIB #R01EB022230), we have developed ultrasmall nanocarriers for targeting, imaging, and image-guided surgery of pancreatic neuroendocrine tumors. Importantly, over 80% of the unbound dose was ultimately eliminated into the urine within 24 h post-injection after systemic circulation. This narrows the design of nanocarriers to include a targeting anchor, an imaging moiety, and a distribution domain, and we have worked diligently to create a reciprocal arrangement whereby each chemical composition provides balancing properties to the others. Interestingly, during the evaluation of inclusion complexation, we found that the nanocarriers can deliver other types of drugs including imatinib (Kang et al. Adv Mater, 2020). This result suggests that ultrasmall nanocarriers can also deliver antiviral drugs to the target with reduced side effects due to rapid renal clearance of unbound molecules. Therefore, the ultimate goal in this administrative supplement application is to develop ultrasmall nanotherapeutics that are complexed with antivirals to treat COVID-19. By payloading selected antiviral drugs into the ultrasmall nanocarriers, we will be able to achieve image-guided drug delivery to the respiratory system with reduced side effects due to the rapid renal clearance of unbound drugs. To achieve this goal, we propose 1) to develop renal clearable nanocarriers for antiviral drug delivery and 2) to evaluate the pharmacodynamics and therapeutic efficacy of the nanocarriers in mouse models of coronavirus infection. Armed with the near- infrared fluorophores conjugated on the nanocarrier, we will also monitor the biodistribution and clearance of antivirals as well as their targetability and therapeutic efficacy under the real-time imaging system.

Project Narrative Currently some antiviral drugs including remdesivir, favipiravir, chloroquine, and hydroxychloroquine have been recognized as the promising treatment options against COVID-19. However, clinical studies showed significant adverse effects, including multiple-organ dysfunction syndrome, cardiotoxicity and retinopathy in a portion of patients receiving them. Using ultrasmall, renal-clearable nanoparticles with near-infrared fluorescence imaging, we propose to establish a nanocarrier system for targeted delivery of antiviral drugs to effectively treat COVID- 19 with minimum to no severe side effects.